In the first three years of this investigation, we demonstrated that insulin-dependent early-onset diabetes mellitus of Keeshond dogs is an autosomal recessive heritable disorder of non-obese purebreds occurring between two and six months of age and that it is the result of an islet B cell deficiency. In addition, it was observed that these diabetic dogs have many of the same lesions that are observed in Juvenile onset diabetes mellitus of people. During this same period, we were able to establish a small breeding colony of Keeshonds for reproduction of diabetic dogs. The objective for the renewal period is to continue biochemical, morphological, histological and metabolic characterization of prediabetic, diabetic and pregnant diabetic dogs. Specific aims include: (1) improvement of the reproductive capacity of the diabetic bitch through the use of backcrossing, outcrossing, induction of estrus, superovulation, and ova and embryo transplantation to supply adequate numbers of this valuable animal model for comparative medical research of diabetes mellitus of people by ourselves and other investigators; (2) characterization of vascular lesions in the retina of the diabetic dog by fluorescent angiography; (3) microscopic examination (light and/or EM) of samples of skeletal muscle, kidney, fat, pancreas and major vessels obtained either by biopsy or at necropsy; (4) characterization of hormone profiles including sex hormones (FSH, LH, IRI, IRG); and (5) detection of any alteration in carbohydrate, lipid, and protein metabolism by determining the concentration of various plasma metabolites in fasted dogs (glucose, cholesterol, triglycerides, free fatty acids, phospholipids, glycerol).